title: Extraneuronal monoamine transporter mediates the permissive action of cortisol in the Guinea pig trachea: possible involvement of tracheal chondrocytes.
abstract: Cortisol, a member of glucocorticoids, could potentiate the action of catecholamine by a non-genomic mechanism. Although this permissive effect has been well appreciated in the anti-asthmatic medication, the underlying signaling pathway has remained mysterious. Here, we show that extraneuronal monoamine transporter (EMT), a membraneous reuptake transporter for circulating catecholamine clearance, is the direct target of cortisol in its permissive effect. We found that BSA-conjugated cortisol, which functions as a cortisol but cannot penetrate cell membrane, enhanced the spasmolytic effect of β-adrenoceptor agonist (isoprenaline) in histamine-sensitized tracheal spirals of guinea pigs, and pharmacological inhibition of EMT with famotidine was powerful enough to imitate the permissive action of cortisol. To our surprise, EMT protein expression was high in the chondrocytes of tracheal cartilage, but was undetectable in tracheal smooth muscle cells. The functionality of EMT was further confirmed with measurement of catecholamine uptake by tracheal chondrocytes. Moreover, cortisol-initiated membrane signaling could activate protein kinase C (PKC), which phosphorylates EMT and induces its internalization via a lipid raft-dependent pathway. Both of the mechanisms slow down the reuptake process by chondrocytes, leading to extracellular catecholamine accumulation and results in a more profound adrenergic signaling activation in tracheal smooth muscle cells. Thus, an EMT-centered pathway was proposed to explain the permissive action of cortisol. Collectively, our results highlight the role of EMT in the crosstalk between glucocorticoid and catecholamine. EMT may represent a promising target for adrenergic signaling modulation.
authors.affiliation: Department of Medicine, Peking Union Medical College, Chinese Academy of Medical Sciences, Beijing, China.
authors.forename: Chen
authors.initials: C
authors.lastname: Wang
authors.forename: Wenying
authors.initials: W
authors.lastname: Qiu
authors.forename: Yiqing
authors.initials: Y
authors.lastname: Zheng
authors.forename: Hui
authors.initials: H
authors.lastname: Li
authors.forename: Yijia
authors.initials: Y
authors.lastname: Li
authors.forename: Bing
authors.initials: B
authors.lastname: Feng
authors.forename: Shu
authors.initials: S
authors.lastname: Guo
authors.forename: Li
authors.initials: L
authors.lastname: Yan
authors.forename: Ji-Min
authors.initials: JM
authors.lastname: Cao
mesh_terms: D000595:Amino Acid Sequence; D000818:Animals; D002395:Catecholamines / Q000378:metabolism; D002462:Cell Membrane / Q000187:drug effects / Q000378:metabolism; D019902:Chondrocytes / Q000187:drug effects / Q000378:metabolism; D015870:Gene Expression; D006168:Guinea Pigs; D006854:Hydrocortisone / Q000494:pharmacology*; D008564:Membrane Potentials / Q000187:drug effects; D008954:Models, Biological; D008958:Models, Molecular; D032389:Myocytes, Smooth Muscle / Q000187:drug effects / Q000378:metabolism; D027701:Organic Cation Transport Proteins / Q000737:chemistry / Q000235:genetics / Q000378:metabolism*; D010766:Phosphorylation; D011487:Protein Conformation; D011493:Protein Kinase C / Q000378:metabolism; D051381:Rats; D015398:Signal Transduction; D014132:Trachea / Q000187:drug effects* / Q000378:metabolism*; D059467:Transcriptome; D000099254:Organic Cation Transporter 3
chemical_list: D002395:Catecholamines; D006854:Hydrocortisone; D027701:Organic Cation Transport Proteins; D011493:Protein Kinase C; D000099254:Organic Cation Transporter 3